Androgens are generally known as the male sex hormones. The androgenic hormones are steroids, which are produced in adult males by the testes and adult females by ovarian theca cells; and a lesser amount by the cortex of the adrenal gland or can be synthesized in the laboratory. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern The endogenous steroidal androgens include testosterone and dihydrotestosterone (“DHT”). Testosterone is the principal steroid secreted by the testes and is the primary circulating androgen found in the plasma of adult males. Under normal physiological circumstances males produce much more testosterone than females. Testosterone is converted to DHT by the enzyme 5-alpha-reductase in many peripheral tissues. DHT is thus thought to serve as the intracellular mediator for most androgen actions.
The gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
It has been found that androgen and/or gonadotropin suppression or abrogation may result in beneficial effects, in a number of diseases and clinical applications, in males and in females.
In men these diseases or disorders, include, but are not limited to benign prostatic hyperplasia (BPH), metastatic prostatic carcinoma, breast cancer, testicular cancer, androgen dependent acne, hypertrichosis, seborrhoea, male pattern baldness and precocious puberty in boys.
In women, androgen and/or gonadotropin suppression or abrogation, has been shown to be therapeutic in clinical settings, such as, for example, in treating Polycystic Ovarian Syndrome (PCOS), endometriosis, adenomyosis, uterine fibroids, heavy menstrual bleeding, hirsutism, androgen dependent acne, seborrhoea, female androgenetic alopecia and hypertrichosis, gonadal steroid-dependent neoplasm (breast cancer, ovary cancer, etc.), gonadotropin-producing pituitary adenoma, premenstrual syndrome and sterility (e.g. assisted reproductive techniques such as in vitro fertilization). Other related conditions affecting women are pre-eclampsia and pregnancy prevention (contraception), and for both sexes, hidradenitis suppurativa and hot flushes.
As is the case in male and female subjects, however, gonadotropin and androgen suppression (also called androgen deprivation) is accompanied by a variety of undesirable clinical conditions and symptoms. For males receiving gonadotrophin releasing hormone (GnRH) agonists these initially cause a flare of increased androgen production that in patients with sex-hormone sensitive cancers may cause a short term increase in tumour growth and if the cancer has spread to the bone it may result in pain. These agents are also injected so there could be soreness, swelling and redness at the injection site. Other side effects that are also associated with GnRH antagonists are for example reduced or absent libido, impotence, shrinkage of testicles and penis, hot flushes, breast tenderness or growth of breasts, osteoporosis, anemia, cognitive reduction, muscle mass loss, weight gain, fatigue, elevated cholesterol and depression.
For male subjects administered 5-alpha-reductase inhibitors side effects are sexual in nature for example erectile dysfunction, decreased libido, reduced ejaculate and breast enlargement or tenderness. These drugs can also lower levels of Prostate-Specific Antigen (PSA) thereby interfering with the results of this analyte utilised to detect prostate cancer. Male and female subjects may also experience with spironolactone breast tenderness, menstrual irregularities (females only), fatigue, dizziness, confusion, nausea and vomiting, headache, hypotension, diarrhoea and possibly hyperkalemia. Cyproterone acetate can cause oligomenorrhea (females only), melasma, fluid retention, nausea and vomiting; this drug is also in rarer cases associated with liver hepatotoxicity and clotting disorders. Flutamide administration may lead to breast tenderness, gastrointestinal upset, hot flashes, and decreased libido; it has a serious potential side-effect of hepatotoxicity. Females taking combined oral contraceptives may experience metrorrhagia, nausea, vomiting, breast tenderness and headaches; and more rarely blood clots, myocardial infarctions, stroke, abnormal lipid indices, glucose intolerance and hypertension.
New innovative approaches are urgently needed at both the basic science and clinical levels to develop compositions and treatment regimens, which provide the beneficial effects of androgen and/or gonadotropins suppression or abrogation, without the deleterious side-effects associated with the current treatments for sex-hormone dependent diseases.
Tachykinins belong to a family of short peptides that are widely distributed in the mammalian central and peripheral nervous system (Bertrand and Geppetti, Trends Pharmacol. Sci. 17: 255-259 (1996)). They share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. The three major tachykinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) with preferential affinity for respectively three distinct receptor subtypes, termed NK-1, NK-2, and NK-3.
Compounds showing selective affinity simultaneously to both NK-1 and NK-3 receptors namely dual NK-1/NK-3 receptor antagonists are being developed for the treatment of both schizophrenia and substance abuse disorders.
Prior to the present invention, however it has not been disclosed or suggested that a dual NK-1/NK-3 receptor antagonist according to the present invention would be useful in the treatment of sex-hormone dependent diseases in which decreased levels of androgens and gonadotropins are desired.